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United States Patent |
5,234,939
|
Capiris
,   et al.
|
August 10, 1993
|
3,5-di-tertiary-butyl-4-hydroxyphenyl imidazolyl methanones and related
compounds as antiinflammatory agents
Abstract
The novel 3,5-di-tertiary-butyl 4-hydroxyphenylimidazolyl methanones and
methanone oximes of the present invention are antiinflammatory agents
having activity as inhibitors of 5-lipoxygenase, cyclooxygenase or both.
Inventors:
|
Capiris; Thomas (Plymouth, MI);
Connor; David T. (Ann Arbor, MI);
Sircar; Jagadish C. (Ann Arbor, MI)
|
Assignee:
|
Warner-Lambert Company (Morris Plains, NJ)
|
Appl. No.:
|
777980 |
Filed:
|
October 17, 1991 |
Current U.S. Class: |
514/400; 514/406; 548/333.5; 548/334.5; 548/374.1 |
Intern'l Class: |
C07D 231/10; C07D 233/64; A61K 031/415 |
Field of Search: |
548/343,378,333.5,334.5,374.1
514/400,406
|
References Cited
U.S. Patent Documents
4535165 | Aug., 1985 | Moore | 514/365.
|
4810716 | Mar., 1989 | Connor | 514/365.
|
5086064 | Feb., 1992 | Capiris | 514/365.
|
5102897 | Apr., 1992 | Boschelli | 514/361.
|
Foreign Patent Documents |
0059090 | Sep., 1982 | EP.
| |
0189771 | Aug., 1986 | EP.
| |
0269981 | Jun., 1988 | EP.
| |
Other References
Milaev, Zh Obshch Khim, 50, (2) 473 (1980).
EPO 91 104 797 (corresponding) Search Report.
Derwent Abstract No. 88-326016/46 (J63239-273-A).
Derwent Abstract No. 87-285927/41 (EP 241-043-A).
Derwent Abstract No. 83-786513/41 (J58148-858-A).
Derwent Abstract No. 19743 D/12 (EP 24-829).
Derwent Abstract No. 88-199352/29 (EP 274-867-A).
|
Primary Examiner: Gerstl; Robert
Attorney, Agent or Firm: Thierstein; Joan, Daignault; Ronald A.
Parent Case Text
This is a divisional application of U.S. Ser. No. 07/646,411, filed Jan.
31, 1991, now U.S. Pat. No. 5,086,064, which is a continuation-in-part of
U.S. application Ser. No. 07/500,175, filed Mar. 27, 1990, now abandoned.
Claims
I claim:
1. A compound of the formula
##STR14##
and a pharmaceutically acceptable base or acid addition salt thereof;
wherein
Z is 0, NOH, or NOCH.sub.3;
Ar is
##STR15##
wherein X is NR.sub.1 ;
R is hydrogen, lower alkyl, halogen, CO.sub.2 R.sub.2 or
##STR16##
wherein R.sub.1 is hydrogen or lower alkyl; and
R.sub.2 and R.sub.3 are independently hydrogen or lower alkyl; and
n is an integer of one or two with the proviso that when n is two then R
cannot be CO.sub.2 R.sub.2 or
##STR17##
2. A compound of claim 1 wherein Z is 0 and Ar is as defined above.
3. A compound of claim 1 wherein Z is NOH and Ar is as defined above.
4. A compound of claim 1 wherein Z is NOCH.sub.3 and Ar is as defined
above.
5. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-pyrazol 3-yl-methanone.
6. A compound of claim 1 which is [3,5-bis(1,1-dimethylethyl)-4
hydroxyphenyl]-1H-pyrazol 3-yl-methanone oxime.
7. A compound of claim 1 which is [3,5-bis(1,1-dimethylethyl)-4
hydroxyphenyl](5-chloro I,3-dimethyl-1 H-pyrazol-4-yl)methanone.
8. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-1H-imidazol-2-yl-methanone.
9. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl-methanone
oxime.
10. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol-2-yl)met
hanone.
11. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol-2-yl)met
hanone, oxime.
12. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-chloro-1,3-dimethyl-1H-pyra
zol-4-yl)methanone oxime.
13. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-4-carboxyimidazol-2-yl
methanone.
14. A compound of claim 1 which is 2-[[3,5
bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazole 5-carboxylic acid
monohydrochloride.
15. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-(5-chloro-1,3-dimethyl-1H-pyr
azol-4 yl)methanone, O-methyloxime.
16. A compound of claim 1 which is 2-[[3,5
bis(1,1-dimethylethyl)-4-hydroxyphenyl](hydroxyimino)methyl]-1H-imidazole-
5-carboxylic acid.
17. A compound of claim 1 which is
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl Methanone,
O-methyloxime.
18. A compound of claim 1 which is [3,5
bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl)-1H-imidazol-2-yl
methanone, O-methyloxime.
19. A compound of claim 1 which is [3,5-bis(1,1-dimethylethyl)-4
hydroxyphenyl]-1H-pyrazol 3 yl methanone, O-methyloxime.
20. A pharmaceutical composition for use as an inhibitor of 5-lipoxygenase,
cyclooxygenase, or both comprising a 5-lipoxygenase, cyclooxygenase or
both inhibiting amount of a compound of claim 1 and a pharmaceutically
acceptable carrier.
21. A method for treating an inflammatory disease or condition in a human
suffering therefrom which comprises administering a compound of claim 1 in
unit dosage form.
22. A pharmaceutical composition which comprises a compound of claim 1 and
a nonsteroidal antiinflammatory agent in a weight ratio of from 1000 to 1
to 1 to 1000.
Description
BACKGROUND OF THE INVENTION
3,5-Di-tertiary-butyl-4-hydroxyphenyl is disclosed as a moiety in a variety
of compounds.
For example, copending U.S. application Ser. No. 395,165 discloses the
moiety in its styryl pyrazoles, isoxazoles, isothiazoles, or imidazoles.
However, the present compounds differ from this disclosure by the
methanone group or the methanone oxime between the 3,5 di-tertiary
4-hydroxyphenyl and each of a thiazolyl, oxazolyl or imidazolyl ring.
Other references disclose compounds combining a
3,5-di-tertiary-butyl-4-hydroxyphenyl with various other rings such as
thiadiazoles, oxadiazoles or triazoles. See copending U.S. application
Ser. No. 07/426,814, which further cites other such combinations. J6
3239-273-A, described in Derwent Abstract Number 88-326016/46, includes an
imidazole and phenyl (optionally substituted) bridged by methylene or
carbonyl. EP 241-043A shows thiazolyl, oxazolyl, and imidazolyl and phenyl
(optionally substituted) bridged by various alkylenyl or alkenylenyl
chains interrupted by a C(Z) group where Z is O, S, NOR.sub.3 or NH. An
oxazole or imidazole ring is attached by a bond to
3,5-di-tert-butyl-4-hydroxyphenyl in J5 8148-858-A, described in Derwent
Abstract Number 83-786513/41, or by CO or CHR.sub.5 in EP24-829 of Derwent
Abstract Number 19743 D/12. However, such references differ from the
present invention in both the heteroaryl ring moiety and the substituent
between the heteroaryl ring and the 3,5-di-tertiary-butyl-4-hydroxyphenyl
moiety. The present invention is limited to rings having two heteroatoms
and a methanone or methanone oxime between the rings.
Finally, a very broad generic disclosure relating a heteroaryl and various
bridging groups to a phenyl not including a
3,5-di-tert-butyl-4-hydroxyphenyl is shown in EP 274-867A of Derwent
Abstract Number 88-199351-29.
SUMMARY OF THE INVENTION
The present invention is a novel compound of the formula (I)
##STR1##
and a pharmaceutically acceptable base or acid addition salt thereof; in
which
Z is O, NOH or NOCH.sub.3 ;
Ar is
##STR2##
wherein
X is NR.sub.1, O, or S;
R is independently hydrogen, lower alkyl, halogen, CO.sub.2 R.sub.2, or
##STR3##
wherein R.sub.1 is hydrogen or lower alkyl, R.sub.2 and R.sub.3 are
independently hydrogen or lower alkyl; and n is an integer of one or two
with the proviso that when n is two then R cannot be CO.sub.2 R.sub.2 or
##STR4##
The present invention is also a pharmaceutical composition for treating a
disease or condition, such as rheumatoid arthritis, osteoarthritis, other
inflammatory conditions, psoriasis, allergic diseases, inflammatory bowel
disease, GI ulcers, cardiovascular conditions including ischemic heart
disease and atherosclerosis, and ischemia-induced cell damage,
particularly brain damage caused by stroke, preferably an inflammatory
disease or condition, comprising an antiinflammatory, antipsoriatic,
antiallergy, antiulcer, or antiischemic, antiatherosclerotic, or
cytoprotective amount of the compound of the formula I or a
pharmaceutically acceptable salt thereof as defined above and a
pharmaceutically acceptable carrier.
The present invention is also a method of treating a disease or condition
as noted above in a mammal, particularly a human, suffering therefrom
which comprises administering a compound of the formula I or salt thereof
as defined above in unit dosage form.
The invention also provides for use of any such compound of formula I or
salt thereof in the manufacture of a medical therapeutic agent.
The pharmaceutical composition or method of treating which is the present
invention is meant to include what is understood to be prophylactic to one
of a foregoing named disease or condition.
The compounds of the formula I have activity as inhibitors of
5-lipoxygenase, cyclooxygenase or both to provide the use for the
pharmaceutical composition and methods of the present invention.
The preferred compounds of the formula I are
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)methanon
e,
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone, and
[3,5-Bis(1,1
dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)methanone,
O-methyloxime.
More preferred compounds are
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone and
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)methanon
e, O-methyloxime.
The most preferred compound is
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone.
A DETAILED DESCRIPTION OF THE INVENTION
In the present invention "lower alkyl is alkyl of from one to six carbons,
inclusive, and means methyl, ethyl, propyl, butyl, pentyl, or hexyl and
isomers thereof.
Halogen is chloro, iodo, bromo or fluoro.
Me is methyl.
The compounds of the invention may contain geometric or optical isomers.
Thus, the invention includes the individual isomers and mixtures thereof.
The individual isomers may be prepared or isolated by methods known in the
art.
The compounds of the invention may contain an asymmetric carbon atom,
particularly, for example, at the R substituent of the compound of formula
I, which is CHR.sub.3 CO.sub.2 R.sub.2. Thus, the invention includes
individual enantiomers, the pure S, the pure R isomer, and mixtures
thereof. The individual enantiomers may be prepared or isolated by methods
known in the art. Likewise diastereomers are included in the invention, if
possible, both as individuals or mixtures thereof.
A tautomeric form of selected compounds of formula I would be recognized by
an ordinarily skilled artisan to be within the present invention.
The compounds of formula I are useful both in the free base and where
possible the free acid form or in the form of base salts thereof, as well
as in the form of acid addition salts. All forms are within the scope of
the invention. In practice, use of the salt form amounts to use of the
acid or free base form. Appropriate pharmaceutically acceptable salts
within the scope of the invention are those derived from mineral acids
such as hydrochloric acid and sulfuric acid; and organic acids such as
methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and
the like, giving the hydrochloride, sulfamate, methanesulfonate,
benzenesulfonate, p-toluenesulfonate, and the like, respectively or those
derived from bases such as suitable organic and inorganic bases. Examples
of suitable inorganic bases for the formation of salts of compounds of
this invention include the hydroxides, carbonates, and bicarbonates of
ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc,
and the like.
Salts may also be formed with suitable organic bases. Bases suitable for
the formation of pharmaceutically acceptable base addition salts with
compounds of the present invention include organic bases which are
nontoxic and strong enough to form such salts. These organic bases form a
class whose limits are readily understood by those skilled in the art.
Merely for purposes of illustration, the class may be said to include
mono-, di-, and trialkylamines such as methylamine, dimethylamine, and
triethylamine; mono-, di-, or trihydroxyalkylamines such as mono-, di-,
and triethanolamine; amino acids such as arginine, and lysine; choline;
guanidine; N-methylglucosamine; N-methylpiperazine; morpholine;
ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane;
and the like. (See, for example, "Pharmaceutical Salts," J. Pharm. Sci.,
66(1), 1-19 (1977.))
The acid addition salts of said basic compounds are prepared either by
dissolving the free base of compound I in aqueous or aqueous alcohol
solution or other suitable solvents containing the appropriate acid or
base and isolating the salt by evaporating the solution, or by reacting
the free base of compound I with an acid as well as reacting compound I
having an acid group thereon with a base such that the reactions are in an
organic solvent, in which case the salt separates directly or can be
obtained by concentration of the solution.
The base salts of compounds of formula I described above are prepared by
reacting the appropriate base with a stoichiometric equivalent of the acid
compounds of formula I to obtain pharmacologically acceptable base salts
thereof.
The acid solution salts of said basic compounds are prepared either by
dissolving the free base in aqueous or aqueous alcohol solution or other
suitable solvents containing the appropriate acid and isolating the salt
by evaporating the solution, or by reacting the free base and acid in an
organic solvent, in which case the salt separates directly or can be
obtained by concentration of the solution.
The base salts of compounds of formula I described above are prepared by
reacting the appropriate base with a stoichiometric equivalent of the acid
compounds of formula I to obtain pharmacologically acceptable base salts
thereof.
The acid solution salts of said basic compounds are prepared either by
dissolving the free base in aqueous or aqueous alcohol solution or other
suitable solvents containing the appropriate acid and isolating the salt
by evaporating the solution, or by reacting the free base and acid in an
organic solvent, in which case the salt separates directly or can be
obtained by concentration of the solution.
The compounds of this invention may also exist in hydrated or solvated
forms. Again, in practice, use of any of these forms amounts to the free
base or acid form.
The usefulness of the compounds of the present invention as inhibitors of
the 5-lipoxygenase enzyme, cyclooxygenase, or in treating related diseases
or conditions may be demonstrated by their effectiveness in various
standard test procedures. A description of each procedure follows.
ARBL/ARBC Cell 5-Lipoxygenase and Cyclooxygenase Assays
Materials
The rat basophilic leukemia cell line (RBL-1) was obtained from the
American Type Culture Collection (Rockville, Md.).
Radioimmunoassay (RIA) kits of LTB4 and PGF.sub.2.alpha. were obtained from
Amersham (Arlington Heights, Ill.) and Seragen (Boston, Mass.),
respectively.
All tissue culture media were obtained from GIBCO (Grand Island, N.Y.).
Method
RBL-1 cells are grown in suspension culture in Eagle's minimum essential
medium supplemented with 12% fetal bovine serum at 37.degree. C. in an
incubator supplied with air-5% carbon dioxide. Cells are harvested by
centrifugation. They are washed with cold phosphate buffered saline pH 7.4
(PBS; NaCl, 7.1 g; Na.sub.2 HPO.sub.4, 1.15 g; KH.sub.2 PO.sub.4, 0.2 g;
and KCl, 0.2 g/L). Cells are finally suspended in PBS containing 1.0 mM
calcium at a density of 2.times.10.sup.6 cells/mL. Cells are incubated
with and without test agent (in DMSO) (1% DMSO is without effect on
arachidonic acid metabolism) for 10 minutes at room temperature. Calcium
ionophore A23187 (5 .mu.M) is added and cells are incubated for 7 minutes
at 37.degree. C. The reaction is stopped by chilling the tubes on ice for
10 minutes. Cells are separated by centrifugation and the supernatant is
stored at -20.degree. C. Aliquots (100 .mu. L) are analyzed for LTB.sub.4
and PGF.sub.2.alpha. using radioimmunoassay kits as provided by the
supplier.
Table I contains biochemical data obtained from this whole cell assay as
IC.sub.50 s which are calculated as the amount of test compound causing
50% inhibition or % of inhibition at the named micromoles (.mu.M) of LTB14
or PGF.sub.2.alpha. formation.
Carrageenan-Induced Rat Foot Paw Edema-2 (CFE-2) Assay: Protocol
Carageenan solution (1% w/v) is prepared by dissolving 100 mg carrageenan
(Marine Colloidal Div., Springfield, N.J.) in 10 mL of sterile saline
(0.9%) solution (Travenol). The solution is vortexed for 30 to 45 minutes.
Animals are dosed with compound 1 hour before carrageenan challenge. Foot
paw edema is induced by injecting 0.10 mL of the 1% carrageenan
subcutaneously into the plantar portion of the right hind paw of each rat
under light anesthesia. Initial foot paw volume is measured immediately
following carrageenan challenge using mercury plethysmography (Buxco
Electronics). Edema is measured 5 hours after carrageenan. The difference
between the 5-hour and the initial paw volume is expressed as delta edema.
The delta edema for each test group of animals is used to calculate the
percent inhibition of edema achieved by the compound at the test dose
compared with the vehicle control group. The data in Table I (the dose at
which swelling is inhibited by the noted percent) is calculated by probit
analysis for the dose at which percent inhibition occurs.
TABLE I
______________________________________
##STR5##
Example
IC.sub.50 (.mu.M)
Number Ar Z ARBL ARBC CFE
______________________________________
##STR6## O 0.83.sup.a
0.06.sup.c
37% @ 3 mg/ kg
4
##STR7## O 91%.sup.b @ 10
91%.sup.d @ 10
11
##STR8## NOH N @ 10.sup.b
N @ 10.sup.d
14
##STR9## NOCH.sub.3
100%.sup.b @ 10
97%.sup.d @ 10
______________________________________
.sup.a IC.sub.50 for LTB.sub.4 inhibition.
.sup.b Percent inhibition of LTB.sub.4 @ 10 .mu.M (N means not active at
the dose tested).
.sup.c IC.sub.50 for PGF.sub.2.alpha..
.sup.d Percent inhibition of PGF.sub.2.alpha. @ 10 .mu.M (N means not
active at the dose tested).
Accordingly, the present invention also includes a pharmaceutical
composition for treating one of the above diseases or conditions
comprising an antidisease or anticondition effective amount of a compound
of the formula I or salt thereof as defined above together with a
pharmaceutically acceptable carrier.
The present invention further includes a method for treating one of the
above named diseases or conditions in mammals, including man, suffering
therefrom comprising administering to such mammals either orally or
parenterally, preferably oral, a corresponding pharmaceutical composition
containing compounds of the formula I or salt thereof.
A physician or veterinarian of ordinary skill readily determines a subject
who is exhibiting symptoms of any one or more of the diseases described
above. Regardless of the route of administration selected, the compounds
of the present invention of the formula I as described in pharmaceutical
compositions above are formulated into pharmaceutically acceptable dosage
forms by conventional methods known to the pharmaceutical art.
The compounds can be administered in such oral unit dosage forms as
tablets, capsules, pills, powders, or granules. They also may be
administered rectally or vaginally in such forms as suppositories or
bougies; they may also be introduced parenterally (e.g., subcutaneously,
intravenously, or intramuscularly) using forms known to the pharmaceutical
art. They are also introduced directly to an affected area (e.g., in the
form of eye drops or by inhalation). For the treatment of asthma or
allergies, particularly dermatological disorders such as erythema,
psoriasis, and acne, the compounds may also be administered topically in
the form of ointments, gels, or the like. However, in general, the
preferred route of administration is oral.
An effective but nontoxic quantity of the compound is employed in
treatment. The ordinarily skilled physician or veterinarian will readily
determine and prescribe the effective amount of the compound to prevent or
arrest the progress of the condition for which treatment is administered.
In so proceeding, the physician or veterinarian could employe relatively
low dosages at first, subsequently increasing the dose until a maximum
response is obtained.
In determining when a lipoxygenase, cyclooxygenase, or dual
lipoxygenase/cyclooxygenase inhibitor is indicated, of course inter aIia,
the particular condition in question and its severity, as well as the age,
sex, weight, and the like of the subject to be treated, must be taken into
consideration and this determination is within the skill of the attendant
physician.
For medical use, the amount required of a compound of formula (I) or
pharmacologically acceptable salt thereof to achieve a therapeutic effect
will, of course, vary both with the particular compound, the route of
administration, the mammal under treatment, and the particular disorder or
disease concerned. A suitable dose of a compound of formula (I) or
pharmacologically acceptable salt thereof for a mammal suffering from, or
likely to suffer from any condition as described hereinbefore is 0.1 .mu.g
to 500 mg of the compound per kilogram body weight. In the case of
systemic administration, the dose may be in the range of 0.5 to 500 mg of
the compound per kilogram body weight, the most preferred dosage being 0.5
to 50 mg/kg of mammal body weight administered two to three times daily.
In the case of topical administration, e.g., to the skin or eye, a
suitable dose may be in the range 0.1 ng to 100 .mu.g of the compound per
kilogram, typically about 0.1 .mu.g/kg.
In the case of oral dosing for the treatment of prophylaxis of arthritis or
inflammation in general, due to any course, a suitable dose of a compound
of formula (I) or physiologically acceptable salt thereof, may be as
specified in the preceding paragraph, but most preferably is from 1 mg to
10 mg of the compound per kilogram, the most preferred dosage being from 1
mg to 5 mg/kg of mammal body weight, for example, from 1 to 2 mg/kg.
It is understood that the ordinarily skilled physician or veterinarian will
readily determine and prescribe the effective amount of the compound to
prevent or arrest the progress of the condition for which treatment is
administered. In so proceeding, the physician or veterinarian could employ
relatively low doses at first, subsequently increasing the dose until a
maximum response is obtained.
While it is possible for an active ingredient to be administered alone, it
is preferable to present it as a pharmaceutical formulation comprising a
compound of formula (I) or a pharmacologically acceptable acid addition or
base salt thereof and a pharmacologically acceptable carrier therefor.
Such formulations constitute a further feature of the present invention.
In addition to the compounds of formula I, the pharmaceutical compositions
can also contain other active ingredients, such as cyclooxygenase
inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), peripheral
analgesic agents such as zomepirac, diflunisal, and the like. The weight
ratio of the compound of the formula I to the second active ingredient may
be varied and will depend upon the effective dose of each ingredient.
Generally, an effective dose of each will be used. Thus, for example, when
a compound of the formula I is combined with an NSAID, the weight ratio of
the compound of the formula I to the NSAID will generally range from about
1000:1 to about 1:1000, preferably about 200:1 to about 1:200.
Combinations of a compound of the formula I and other active ingredients
will generally also be within the aforementioned range, but in each case,
an effective dose of each active ingredient should be used.
Combinations of a compound of the formula I and other active ingredients
will generally be in the aforementioned ratios.
NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives; and
(5) the oxicams or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise: ibuprofen,
ibuprofen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen
flurbiprofen, fenoprofen, fenbufen, pirprofen, carprofen, oxaprizin,
pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen,
fluprofen, and bucloxic acid. Structurally related propionic acid
derivatives having similar analgesic and antiinflammatory properties are
also intended to be included in this group.
Thus, "propionic acid derivatives" as defined herein are nonnarcotic
analgesics/nonsteroidal antiinflammatory drugs having a free
--CH(CH.sub.3)COOH or --CH.sub.2 CH.sub.2 COOH group (which optionally can
be in the form of a pharmaceutically acceptable salt group, e.g.,
--CH(CH.sub.3)COO.sup.- NA.sup.+ or --CH.sub.CH.sub.2 COO.sup.-Na.sup.+),
typically attached directly or via a carbonyl function to a ring system,
preferably to an aromatic ring system.
The acetic acid derivatives which may be used comprise: indomethacin, which
is a preferred NSAID, sulindac, tolmetin, zomepirac, diclofenac,
fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,
zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozic acid.
Structurally related acetic acid derivatives having similar analgesic and
antiinflammatory properties are also intended to be encompassed by this
group.
Thus, "acetic acid derivatives" as defined herein are nonnarcotic
analgesics/nonsteroidal antiinflammatory drugs having a free --CH.sub.2
COOH group (which optionally can be in the form of a pharmaceutically
acceptable salt group, e.g., --CH.sub.2 COO.sup.- Na.sup.+), typically
attached directly to a ring system, preferably to an aromatic or
heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise: mefenamic acid,
meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid.
Structurally related fenamic acid derivatives having similar analgesic and
antiinflammatory properties are also intended to be encompassed by this
group.
Thus, "fenamic acid derivatives" as defined herein are nonnarcotic
analgesics/nonsteroidal antiinflammatory drugs which contain the basic
structure:
##STR10##
which can bear a variety of substituents and in which the free --COOH
group can be in the form of a pharmaceutically acceptable salt group,
e.g., --COO.sup.- Na.sup.+.
The biphenylcarboxylic acid derivatives which can be used comprise:
diflunisal and flufenisal. Structurally related biphenylcarboxylic acid
derivatives having similar analgesic and antiinflammatory properties are
also intended to be encompassed by this group.
Thus, "biphenylcarboxylic acid derivatives" as defined herein are
nonnarcotic analgesics/nonsteroidal antiinflammatory drugs which contain
the basic structure:
##STR11##
which can bear a variety of substituents and in which the free --COOH
group can be in the form of a pharmaceutically acceptable salt group,
e.g., --COO.sup.- Na.sup.+.
The oxicams which can be used in the present invention comprise: piroxicam,
sudoxicam, isoxicam, and 4-hydroxyl-1,2-benzothiazine 1,1-dioxide
4-(N-phenyl)-carboxamide. Structurally related oxicams having similar
analgesic and antiinflammatory properties are also intended to be
encompassed by this group.
Thus, "oxicams" as defined herein are nonnarcotic analgesics/nonsteroidal
antiinflammatory drugs which have the general formula:
##STR12##
wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used: acemetacin, alminoprofen, amfenac
sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac
lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen,
cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet,
delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,
difenpyramide, emorfazone, enfenamic acid, enolicam, epirazole,
etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,
fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,
flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal,
furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,
isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,
lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin, clonixinate,
meclofenamate sodium, meseclazone, microprofen, nabumetone, nictindole,
nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin, perisoxal citrate,
pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, pirprofen,
pranoprofen, proglumetacin, maleate, proquazone, pyridoxiprofen,
sudoxicam, suprofen, talmetacin, talniflumate, tenoxicam,
thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramide HCl,
tiflamizole, timegadine, toxaprofen, tolfenamic acid, tolpadol, tryptamid,
ufenamate, and zidometacin.
Finally, NSAIDs which may also be used include the salicylates,
specifically aspirin, and the phenylbutazones, and pharmaceutically
acceptable salts thereof.
Pharmaceutical compositions comprising the formula I compounds may also
contain as the second active ingredient, antihistaminic agents such as
benadryl, dramamine, histadyl, phenergan, and the like. Alternatively,
they may include prostaglandin antagonists such as those disclosed in
European Patent Application 11,067 or thromboxane antagonists such as
those disclosed in U.S. Pat. No. 4,237,160. They may also contain
histidine decarboxylase inhibitors such as .alpha.-fluoromethylhistidine,
described in U.S. Pat. No. 4,325,961. The compounds of the formula I may
also be advantageously combined with an H.sub.1 or H.sub.2 -receptor
antagonist, such as for instance cimetidine, ranitidine, terfenadine,
famotidine, temelastine, acrivastine, loratadine, cetrizine, tazifylline,
azelastine, aminothiadiazoles disclosed in EP 81102976.8 and like
compounds, such as those disclosed in U.S. Pat. Nos. 4,283,408; 4,362,736;
4,394,508, and European Patent Application No. 40,696. The pharmaceutical
compositions may also contain a K.sup.+ /H.sup.+ ATPase inhibitor such as
omeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like. Each of
the references referred to in this paragraph is hereby incorporated herein
by reference.
The compounds of the formula I are prepared generally by the following
processes and constitute a further aspect of the present invention.
Generally, the compounds of formula I are prepared by one of the following
methods A:, B: or C: and shown hereinafter in Schemes I, II, or III,
respectively.
##STR13##
General Procedures for the Synthesis of 3,5-Di-tert-butyl-4-hydroxyphenyl
Thiazolyl, Oxazolyl, and Imidazolyl Methanones
The target compounds are prepared by three different methods. One method,
shown in Scheme I above, involves a Friedel-Crafts reaction.
2,6-Di-tert-butylphenol is reacted with the acid chloride at -10.degree.
C. to +20.degree. C. in the presence of a Lewis acid such as AlCl.sub.3,
TiCl.sub.4, or others in solvents like CS.sub.2, 1,2-dichloroethane, and
CCl.sub.4 for 1 hour to 24 hours. The products are isolated by the
standard procedures known in the art and flash chromatographed to purify.
Another method shown in Scheme II above involves anion chemistry. 3,5-Di
tert-butyl-4-[(2-methoxyethoxy)methoxy]benzaldehyde is reacted with slight
excess of anion of the heterocyclic compound at -78.degree. C. to
+10.degree. C. for 1 hour to 20 hours in solvents like THF or ether. The
products are isolated by the techniques known in the art and, if
necessary, purified by flash chromatography. The intermediate carbinol is
oxidized by KMnO.sub.4 in the presence of
tris[2-(2-methoxethoxy)ethyl]amine in solvents like methylene chloride,
chloroform, or carbon tetrachloride at 24.degree. C. for 0.25 hour to 4.0
hours. The isolated product is deprotected using 1% to 10% HCl/MeOH at
24.degree. C. for 0.25 hour to 3 days. Finally, a method shown in Scheme
III also uses anion chemistry. 3,5-Di-tert-butyl 4-hydroxybenzoylchloride
is converted to the corresponding N,O-dimethylhydroxamate by reacting with
N,O dimethylhydroxylamine.HCl and a base such as N-methylpiperidine,
triethylamine, or diisopropylamine in solvents such as CH.sub.2 Cl.sub.2,
CHCl.sub.3, Et.sub.2 O or other organic solvent for 1 to 20 hours. The
N,O-dimethylhydroxamate is then reacted with 2-methoxyethoxymethyl
chloride and 1 to 3 equivalents of diisopropylethylamine in solvent such
as CH.sub.2 Cl.sub.2, CHCl.sub.3 or Et.sub.2l O for 24 to 96 hours at
reflux temperature. The protected N,O-dimethylhydroxamate is reacted with
the anion of the heterocyclic compounds at -78.degree. C. to 25.degree. C.
in solvents such as Et.sub.2 O or THF for 1 to 4 hours. The reaction
mixture is worked up as known in the art and purified by flash
chromatography. The product is deprotected with 1 to 10% HCl/MeOH for 0.25
to 3 days at 24.degree. C. to give the final product.
One of skill in the art would recognize variations in the sequence and
would recognize variations in the appropriate reaction conditions from the
analogous reactions shown or otherwise known which may be appropriately
used in the processes above to make the compounds of the formula I herein.
Introduction and removal of such suitable oxygen protecting groups are well
known in the art of organic chemistry; see for example, "Protective Groups
in Organic Chemistry," J. F. W. McOmie, ed., (New York, 1973), pages 43ff,
95ff, J. F. W. McOmie, Advances in Organic Chemistry, Vol. 3, 159-190
(1963); J. F. W. McOmie, Chem. & Ind., 603 (1979); and T. W. Greene,
"Protective Groups in Organic Synthesis", Wiley (New York), 1981, Chapters
2, 3, and 7.
Examples of suitable oxygen protecting groups are benzyl, trialkylsilyl,
ethoxyethyl, methoxyethoxymethyl, methoxymethyl, trialkylsilylethyl, and
the like.
In the process described herein for the preparation of compounds of this
invention the requirements for protective groups are generally well
recognized by one skilled in the art of organic chemistry, and accordingly
the use of appropriate protecting groups is necessarily implied by the
processes of the charts herein, although such groups may not be expressly
illustrated.
The products of the reactions described herein are isolated by conventional
means such as extraction, distillation, chromatography, and the like.
Starting materials not described herein are available commercially, are
known, or can be prepared by methods known in the art.
The salts of the compounds of formula I described above are prepared by
reacting the appropriate base r acid with a stoichiometric equivalent of
the compounds of formula I.
The invention is further elaborated by the representative examples as
follows. Such examples are not meant to be limiting.
EXAMPLE 1
3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)methanone
To a solution of 20.6 g (0.1 mole) of 2,6-di-tert-butylphenol and 15.6 g
(0.107 mole) of 5-methylisoxazole-3-carboxylic acid chloride in 100 mL of
CS.sub.2 is added 14.3 g (0.107 mole) of AlCl.sub.3 at +5.degree. C.
Vigorous stirring is maintained at that temperature for 1 hour and then at
room temperature for 1 hour. The CS.sub.2 is decanted off and the residue
treated with 350 mL of ice cold 1N HCl and extracted with Et.sub.2 O. The
extracts are washed with saturated NaHCO.sub.3 solution and brine, dried
with Na.sub.2 SO.sub.4 and evaporated to give a mixture of products. The
desired product is separated by flash chromatography (0% to 50% CH.sub.2
Cl.sub.2 /n-hexane) on silica gel to give 4.4 g of the crude ketone which
is recrystallized from n-pentane to give 2.3 g (14%) of pale yellow
crystals, [3,5-bis(1,1 dimethylethyl)- 4-hydroxyphenyl(5
methyl-3-isoxazolyl)methanone, mp 120.degree. C.; .sup.1 H NMR
(CDCl.sub.3) .delta.1.48 (s, 18H, tert butyl), 2.52 (s, 3H, CH.sub.3),
5.85 (s, IH, OH), 6.48 (s, 1H, isoxazole aromatic), 8.23 (s, 2H, phenyl
aromatics); IR (KBr) 1590, 1600, 1650, 3600 cm.sup.-1 ; MS (DEI) m/e 315
(M.sup.+), 300 (M-CH.sub.3).
Anal. for C.sub.19 H.sub.25 NO.sub.3 :
Calcd: C, 72.35; H, 7.99; N, 4.44.
Found: C, 71.96; H, 8.08; N, 4.34.
EXAMPLE 2
3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde
A mixture of 11.7 g (0.05 mole) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde
and 19.4 g (0.15 mole) of diisopropylethylamine in 150 mL of CH.sub.2
Cl.sub.2 is treated with 18.7 g (0.15 mole) of 2-methoxyethoxymethyl
chloride (MEM Cl) and the resulting solution is heated under reflux for 48
hours and evaporated to dryness. The residue is taken up in CH.sub.2
Cl.sub.2, washed with 1N HCl and brine, and dried with MgSO.sub.4. The
solution is evaporated and the residue is filtered through flash grade
silica gel, washing with 1:1 CH.sub.2 Cl.sub.2 /n-hexane. Evaporation
gives a tan oil, 12.2 g of
3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzaldehyde (76%)
which is used without further purification.
.beta..sup.1 H NMR (CDCl.sub.3) .delta.1.4 (s, 18H, tert-butyl), 3.3 (s,
3H, CH.sub.3), 3.5 (m, 2H, CH.sub.2), 3.8 (m, 2H, CH.sub.2), 4.9 (s, 2H,
OCH.sub.2 O), 7.7 (s, 2H, aromatics), 9.8 (s, 1H, CHO).
Anal. for C.sub.19 H.sub.30 O.sub.4 : Calcd: C, 70.77; H, 9.38. Found: C,
70.87; H, 9.33.
EXAMPLE 3
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol-2yl)metha
none
To a solution of 1.67 g (0.0165 mole) of diisopropylamine in 100 mL THF is
added 10.3 mL of a 1.6 M n-BuLi/hexane solution (0.0165 mole) at
-78.degree. C. After 15 minutes at that temperature 1.31 g (0.016 mole) of
1-methylimidazole is slowly added and the reaction mixture is warmed to
+10.degree. C. and then recooled. The MEM-protected aldehyde from Example
2 (4.6 g, 0.0143 mole) in 25 mL THF is added and the reaction mixture is
allowed to remain at room temperature for 17 hours. The reaction mixture
is poured into 350 mL of ice cold 0.5N HCl and extracted with CH.sub.2
Cl.sub.12. The extracts are washed with saturated NaHCO.sub.3 and brine,
dried with Na.sub.2 SO.sub.4, and evaporated. The residue is
recrystallized from Et.sub.2 O - n hexane to give 3.85 g of a white solid
intermediate carbinol, mp 134-136.degree. C.
Anal. for C.sub.23 H.sub.36 N.sub.2 O.sub.4 : Calcd: C, 68.28; H, 8.97; N,
6.93. Found: C, 68.18; H, 8.91; N, 6.83.
A solution of 405 mg (0.001 mole) of this intermediate and 32.3 mg (0.0001
mole) of (tris[2-(2-methoxyethoxy)ethyl]amine in 20 mL of CH.sub.2
Cl.sub.2 at room temperature is treated over a 5-minute period with 316 mg
(0.002 mole) of powdered KMnO.sub.4. The mixture is stirred 2 hours,
filtered through celite, and evaporated to give 0.4 g of a yellow oil, IR
(film) 1645 cm.sup.-1.
The yellow oil is dissolved in 25 mL of 5% (w/v) HCl/MeOH, allowed to stand
at room temperature for 24 hours, and evaporated. The residue is
recrystallized from EtOAc-iPr.sub.2 O to give a white crystalline
hydrochloride. Loss of hydrogen chloride accompanies drying at 110.degree.
C. under high vacuum to give 125 mg of
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol-2-yl)met
hanone, mp 172-174.degree. C. (24% overall yield). .sup.1 H NMR
(DMSO-d.sub.6) .delta.1.42 (s, 18H, tert-butyl), 3.95 (s, 3H, NCH.sub.3),
7.18 (s, 1H, OH), 7.52 (s, 1H, imidazole aromatic), 7.83 (s, 1H, imidazole
aromatic), 8.23 (s, 2H, phenyl aromatic); IR (KBr) 1580, 1630 cm.sup.-1 ;
MS (DEI) m/e 314 (M.sup.+), 299 (M-CH.sub.3).
Anal. for C.sub.19 H.sub.26 N.sub.2 O.sub.2 : Calcd: C, 72.58; H, 8.34; N,
8.91. Found: C, 72.19; H, 8.23; N, 8.53.
EXAMPLE 4
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone
The compound in this example is prepared starting from the compound in
Example 2 and thiazole according to the method reported for Example 3.
There is obtained 1.17 g (29% overall yield) yellowish-white crystals,
[3,5-bis(1,1 dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone, mp
106-108.5.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.49 (s, 18H, tert
butyl), 5.83 (s, 1H, OH, 7.66 (d, J=3.15, IH, thiazole aromatic), 8.06 (d,
J=3.07, 1H, thiazole aromatic), 8.48 (s, 2H, phenyl aromatics); IR (KBr)
1480, 1593, 1639, 3602 cm.sup.-1 ; MS (DEI) m/e 317 (M+), 302.
Anal. for C.sub.18 H.sub.23 NSO.sub.2 : Calcd: C, 68.12; H, 7.31; N, 4.41;
S, 10.10. Found: C, 68.21; H, 7.34; N, 4.40; S, 10.13.
EXAMPLE 5
N-Methoxy-N-methyl-(3,5-di-tert-butyl-4-hydroxy)benzamide
A solution of 62.6 g (0.25 mole) of 3,5-di-tert-butyl-4-hydroxybenzoic acid
in 500 mL CH.sub.2 Cl.sub.2 is treated with 66.19 g (0.527 mole) of oxalyl
chloride and four drops of DMF. After stirring at room temperature for 16
hours the reaction mixture is evaporated to yield a yellow solid which is
dissolved in 200 mL of CH.sub.2 Cl.sub.2. This solution is added, over a
period of 25 minutes, to a solution of 64 g (0.645 mole) of
N-methylpiperidine and 31.6 g (0.324 mole) of N,O-dimethylhydroxylamine
hydrochloride in 400 mL of CH.sub.2 Cl.sub.2 while the temperature is
maintained at +5 to +10.degree. C. The reaction mixture is stirred at room
temperature for 16 hours and then poured into 500 mL of ice cold 5%
Na.sub.2 CO.sub.3. The CH.sub.2 C.sub.2 layer is washed with 5% Na.sub.2
CO.sub.3, 3N HCl and brine, dried with Na.sub.2 SO.sub.4, and evaporated
to yield a yellow solid. Recrystallization from n-hexane gives off-white
crystals, N-methoxy-N-methyl-(3,5-di-tert butyl-4-hydroxy)benzamide, 60.8
g (83%), mp 112-113.5.degree. C.; 1H NMR (CDCl.sub.3) .delta.1.45 (s, 18H,
tert-butyl), 3.34 (s, 3H, NCH.sub.3), 3.63 (s, 3H, OCH.sub.3), 5.49 (s,
IH, OH), 7.57 (s, 2H, aromatics).
Anal. for C.sub.17 H.sub.27 NO.sub.3 : Calcd: C, 69.59; H, 9.28; N, 4.77.
Found: C, 69.71; H, 9.61; N, 4.56.
EXAMPLE 6
N-Methoxy-N-methyl-3,5-di-tert-butyl 4-[(2-methoxyethoxy)methoxy]]benzamide
This compound is prepared from the compound in Example 5 according to the
method reported for the compound in Example 2. It is obtained as an amber
oil in 50% yield of N-methoxy-N
methyl-[3,5-di-tert-butyl-4[(2-methoxyethoxy)methoxy]]benzamide, and is
used without further purification. .sup.1 H NMR (CDCl.sub.3) .delta.1.44
(s, 18H, tert-butyl), 3.35 (s, 3H, C-OCH.sub.3), 3.43 (s, 3H, NCH.sub.3),
3.61 (s, 3H, NOCH.sub.3), 3.63-3.70 (m, 2H, CH.sub.2), 397-4.00 (m, 2H,
CH.sub.2), 5.00 (s, 2H, OCH.sub.2 O), 7.60 (s, 2H, aromatics).
Anal. for C.sub.21 H.sub.35 NO.sub.5 : Calcd: C, 66.11; H, 9.25; N, 3.67.
Found: C, 66.08; H, 9.28; N, 3.35.
EXAMPLE 7
[3,5-bis(1,1-dimethylethyl) 4
hydroxyphenyl](5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methanone
4-Bromo-5-chloro-1,3-dimethylpyrazole (Butler, D. E., DeWald, H. A., J.
Org. Chem., 1971, 36, 2545) (6.3 g, 0.03 mole) in Et.sub.2 O (100 mL) is
cooled to +10.degree. C. and treated rapidly (25 seconds) with 1.6 M
n-butyllithium (20 mL). After stirring this suspension at room temperature
for 15 minutes it is added, all at once, to a solution of
N-methoxy-N-methyl-[3,5-di-tert-butyl-4[(2-methoxyethoxy)methoxy]]benzamid
e (Example 6) (11.43 g, 0.03 mole) in Et.sub.2 O (100 mL) at 70.degree. C.
The reaction mixture is stirred at room temperature for 16 hours and then
treated with 220 mL ice cold 0.4 N HCl. The Et.sub.2 O layer is washed
with saturated NaHCO.sub.3, dried with Na.sub.2 SO.sub.4 and evaporated to
give an amber oil which is allowed to stand for 3 days in 100 mL 5% (w/v)
HCl/MeOH. Evaporation yields an oil which is taken up to Et.sub.2 O,
washed with saturated NaHCO.sub.3 and brine, dried with Na.sub.2 SO.sub.4
and evaporated. The residue is purified by flash chromatography (0-25%
EtOAc/CH.sub.2 Cl.sub.2) on silica gel to yield 7.2 g of the crude
product. Recrystallization from n-hexane affords 3.78 g (35%) of white
crystals, [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](5 chloro
1,3-dimethyl-IH-pyrazol-4-yl)methanone, mp 115.5-117.degree. C.; .sup.1 H
NMR (CDCl.sub.3) .delta.1.45 (s, 18H, tert-butyl), 2.29 (s, 3H,
C-CH.sub.3), 3.85 (s, 3H, N CH.sub.3), 5.75 (s, 1H, OH), 7.68 (s, 2H,
aromatics); IR (KBr) 1421, 1572, 1586, 1625, 1634 cm.sup.-1 ; MS (DEI) m/e
363 (M.sup.+), 347, 157.
Anal. for C.sub.20 H.sub.27 N.sub.2 O.sub.2 Cl: Calcd: C, 66.20; H, 7.50;
N, 7.72; Cl, 9.77. Found: C, 66.04; H, 7.48; N, 7.65; Cl, 10.21.
EXAMPLE 8
3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-pyrazol-3-yl methanone
To a solution of 1-(1-pyrrolidinomethyl)-pyrazole (Katritzky, A. R.;
Rewcastle, G. W.; Fan, W-Q., J. Org. Chem., 1988, 53, 5688) (3.32 g, 0.022
mole) in THF (75 mL) at -70.degree. C. is added 1.6 M n butyllithium (14
mL) over a 20-minute period. After stirring at that temperature 1.5 hours
a solution of N-methoxy-N-methyl-[3,5-di-tert
butyl-4[(2-methoxyethoxy)methoxy]]-benzamide (Example 6) (7.62 g, 0.02
mole) in THF (75 mL) is added over a 30-minute period. The reaction
mixture is allowed to warm to room temperature, treated with ice cold 2 N
HCl (200 mL) and concentrated to remove the THF. The concentrated mixture
is extracted with CH.sub.2 Cl.sub.2. The extracts are washed with
saturated NaHCO.sub.3 and brine, dried with Na.sub.2 SO.sub.4 and
evaporated. The residue is purified by flash chromatography (0-30%
EtOAc/CH.sub.2 Cl.sub.2) on silica gel to give 6.25 g of an oil. This
product is deprotected by allowing to stand in 5% (w/v) HCl/MeOH (150 mL)
for 2 days. The acid solution is evaporated and the residue is taken up in
Et.sub.2 O. The resulting solution is washed with saturated NaHCO.sub.3
and brine, and dried with Na.sub.2 SO.sub.4. The ethereal solution is
concentrated causing the precipitation of 3.62 g (75%) of a white solid,
[3,5-bis(1,1-dimethylethyl)-4-hydroxypheny]-1H-pyrazol-3 yl methanone, mp
216-219.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta.1.42 (s, 18H,
tert-butyl), 6.84 (m, 1H, OH), 8.19 (s, 2H, phenyl aromatics); pyrazole
aromatics and NH appear as several poorly defined signals because of
tautomerization at 7.6-7.9, 13.4, 13.9; IR (KBr) 1430, 1592, 1643
cm.sup.-1 ; MS (DEI) m/e 301 (M.sup.+ +1), 300 (M.sup.+), 95.
Anal. for C.sub.18 H.sub.24 N.sub.2 O.sub.2 : Calcd: C, 71.97; H, 8.05; N,
9.33. Found: C, 71.85; H, 8.13; N, 9.22.
EXAMPLE 9
[3,5 Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl methanone
To a solution of 1 [(dimethylamino)methyl]imidazole (5.66 g, 0.0375 mole)
(See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q, J. Org. Chem. 1988, 53,
5688) in THF (100 mL) at -70.degree. C. is added 1.6 M n-butyllithium (25
mL) over a 20-minute period. The mixture is stirred 1 hour and a solution
of 11.83 g (0.03 mole) of N-methoxy-N
methyl-[3,5-di-tert-butyl-(2-methoxyethoxy)methoxy]]-benzamide (Example 6)
in THF (75 mL) is added slowly. The reaction mixture is stirred at room
temperature for 16 hours, treated with 100 mL ice-cold 2 N HCl and
concentrated to remove with THF. The precipitate is collected, washed with
H.sub.2 O and dried giving 11.6 g of a white solid. A portion of this (7.7
g) is deprotected by allowing it to stand in 120 mL of 5% (w/v) HCl/MeOH
for 24 hours. The acid solution is evaporated. The residue is suspended in
saturated NaHCO.sub.3, filtered off, washed with H.sub.2 O and
recrystallized from MeOH to yield white crystals,
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol 2 yl methanone,
3.8 g (64%), mp 286-288.degree. C.; .sup.1 H NMR (DMSO d.sub.6)
.delta.1.44 (s, 18H, tert-butyl), 7.28 (s, IH, OH), 7.45 (broad singlet,
1H, imidazole), 7.85 (broad singlet, 1H, imidazole), 8.50 (s, 2H, phenyl),
13.22 (broad, 1H, NH); IR (KBr) 1595, 1644, 3603 cm.sup.-1 ; MS (DEI) m/e
301 (M.sup.+ +1), 285 (M-15).
Anal. for C.sub.18 H.sub.24 N.sub.2 O.sub.2 : Calcd: C, 71.97; H, 8.05; N,
9.33. Found: C, 71.95; H, 8.28; N, 9.18.
EXAMPLE 10
[3,5 [3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl
methanone oxime
To a solution of the compound in Example 9 (1.02 g, 0.0034 mole) and 1.74 g
(0.022 mole) of pyridine in 100 mL iPrOH is added 1.18 g (0.017 mole)
hydroxylamine hydrochloride. The reaction mixture is heated under reflux
24 hours and evaporated. The residue is suspended in H.sub.2 O and
extracted with CH.sub.2 Cl.sub.2. The extracts are washed with saturated
NaHCO.sub.3, dried with MgSO.sub.4 and evaporated. The residue is
recrystallized from EtOAc yielding 0.43 g (40%) of a white solid,
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl methanone
oxime, mp 115-116,5.degree. C.; 1H NMR (DMSO-d.sub.6) .delta.1.38 (s, 18H,
tert-butyl), (iPrOH doublet at 1.04 and multiplet at 4.02), 7.31 and 7.41
(two singlets due to oxime isomers, 2H, phenyl aromatics); the imidazole
aromatics, NH and OH appear as very broad and fragmented signals (6.9-7.3,
11.1, 12-12.5) totaling five protons; IR (KBr) 1420, 1440, 1460, 1500,
3350, 3610 cm.sup.-1 : MS (DEI) 316 (M.sup.+ +1), 298 (M-OH), 282.
Anal. for C.sub.18 H.sub.25 N.sub.3 O.sub.2 .multidot.0.3 iPrOH: Calcd: C,
68.08; H, 8.28; N, 12.60. Found: C, 68.00; H, 8.14; N, 12.61.
EXAMPLE 11
[3,5-Bis(1,1-dimethylethyl)-4 hydroxyphenyl]-2-thiazolyl methanone oxime
The compound in this example is prepared from the compound in Example 4
according to the method described for Example 10. There is obtained 0.454
g white solid (55%)
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-thiazolyl methanone oxime,
mp 243-244.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.1.39 (s, 18H,
tert-butyl), 7.19 (s, IH, phenolic OH), 7.41 (s, 2H, phenyl aromatics),
8.03 (two overlapping doublets, 2H, imidazole aromatics), 12.8 (s, IH,
NOH); IR (KBr) 1460, 1485, 3600 cm.sup.-1 ; MS (DEI) 332 (M.sup.+), 317,
302.
Anal. for C.sub.18 H.sub.24 N.sub.2 SO.sub.2 : Calcd: C, 65.04; H, 7.28; N,
8.43; S, 9.65. Found: C, 65.02; H, 7.21; N, 8.19; S, 9.46.
EXAMPLE 12
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol-2-yl)meth
anone oxime
The compound in this example is prepared from the compound in Example 3
according to the procedure described for Example 10. There is obtained
0.28 g (42%) white solid,
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](1-methyl-1H-imidazol
2-yl)methanone oxime, mp 284-286.degree. C.; 1H NMR (DMSO-d.sub.6)
.delta.1.33 (s, 18H, tert-butyl)3.50 (s, 3H, NCH.sub.3), 7.02 (s, 1H,
phenolic OH), 7.25 (two singlets, 4H, aromatics), 11.6 (s, 1H, NOH); IR
(KBr) 1410, 1434, 1472, 3639 cm.sup.-1 ; MS (DEI) 330 (M+1), 312. (M OH),
296.
Anal. for C.sub.19 H.sub.27 N.sub.3 O.sub.2 : Calcd: C, 69.27; H, 8.26; N,
12.76. Found: C, 69.24; H, 8.30; N, 12.44.
EXAMPLE 13
[3,5-Bis(1,1- dimethylethyl)-4-hydroxyphenyl]-1H-pyrazol-3-yl methanone
oxime
This compound is prepared from the compound in Example 8 according to the
procedure described for Example 10. There is obtained 0.49 g (39%) white
solid, [3,5-bis(1,1-dimethylethyl) 4 hydroxyphenyl]-1H-pyrazol-3-yl
methanone oxime, mp 156-163.degree. C.; .sup.1 H NMR (CDCl.sub.3
+DMSO-d.sub.6) .delta.1.44 (s, 18H, tert-butyl), 5.68 (s, 1H, OH), 7.39
(s, 2H, phenyl aromatics), 6.4 and 7.4-7.6 (pyrazole aromatics, 2H, spread
out as multiplet and broad signals due to tautomerism and H-bonding),
11.8-12.6 (broad, OH, NH, 2H); IR (KBr) 1420, 3620 cm.sup.-1 ; MS (DEI)
315 (M ), 300.
Anal. for C.sub.18 H.sub.25 N.sub.3 O.sub.2 .multidot.3H.sub.2 O: Calcd: C,
67.39; H, 8.04; N, 13.10. Found: C, 67.37; H, 8.22; N, 13.11.
EXAMPLE 14
3,5-Bis(1,1-dimethylethyl)-4
hydroxyphenyl](5-methyl-3-isoxazolyl)methanone, O-methyloxime
To a mixture of
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl(5-methyl-3-isoxazolyl)methanon
e (Example 1) (0.725 g, 0.0023 mole) and 1.25 g (0.015 mole) methoxylamine
hydrochloride in 25 mL i-PrOH is added 1.9 g (0.024 mole) pyridine. The
mixture is heated under reflux for 38 hours and evaporated and the residue
is suspended in H.sub.2 O and extracted with Et.sub.2 O. The extracts are
washed with 0.2 N HCl, saturated NaHCO.sub.3, brine, and dried with
Na.sub.2 SO.sub.4. Evaporation yields an oil which is chromatographed on a
Chromatotron apparatus on silica gel (1:1 CH.sub.2 Cl.sub.2 - n-hexane).
The product fraction is evaporated and crystallized with n-pentane to give
0.17 g (22%) white crystals,
3.5-bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-methyl-3-isoxazolyl)
methanone, O-methyloxime, mp 107.5-111.5.degree. C.; 1H NMR (CDCl.sub.3)
.delta.1.42 (s, 18H, tert-butyl), 2.48 (two singlets, 3H, C-CH.sub.3), 4.0
(two singlets, 3H, OCH.sub.3), 5.4 (two singlets, 1H, OH), 6.34 (two
overlapping singlets, 1H, isoxazole), 7.40 (s, 2H, phenyl aromatics); IR
(KBr) 1420, 1600, 3600 cm.sup.-1 ; MS (DEI) 345 (M+1), 329 (M-CH.sub.3),
313, 297.
Anal. for C.sub.20 H.sub.28 N.sub.2 O.sub.3 : Calcd: C, 69.74; H, 8.19; N,
8.13. Found: C, 69.45; H, 8.23; N, 8.06.
EXAMPLE 15
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl](5-chloro-1,3
-dimethyl-1H-pyrazol-4-yl)methanone oxime
This compound is prepared from Example 7 according to the procedure for
Example 10. There is obtained 0.75 g (53%) white crystal,
[3,5-bis(1,1-dimethylethyl)
-4-hydroxyphenyl](5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methanone oxime,
mp >147.degree. C.; 1H NMR (CDCl.sub.3) .delta.1.41 (s, 18H, t-butyl),
2.13 (s, 3H, C-CH.sub.3), 3.87 (s, 3H, N-CH.sub.3), 5.39 (s, 1H, phenolic
OH), 7.35 (s, 2H, aromatics), 8.70 (s, 1H, N-OH); IR (KBr) 1438, 1541,
3631 cm.sup.-1 ; MS (EI) 379 (M+1), 378 (M.sup.+), 377 (M-1), 362 (M-16),
191.
Anal. For C.sub.20 H.sub.28 N.sub.3 O.sub.2 Cl: Calcd: C, 63.56; H, 7.47;
N, 11.12; Cl, 9.38. Found: C, 63.16; H, 7.43; N, 11.02; C., 9.52.
EXAMPLE 16
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-oxazolyl methanone
This compound is prepared from oxazole using the method described in
Example 8. There is obtained 0.378 g (11%) white crystals, mp
127-130.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.50 (s, 18H,
tert-butyl), 5.87 (s, 1H, OH), 7.40 (s, 1H, oxazole), 7.87 (s, 1H,
oxazole), 8.45 (s, 2H, phenyl); IR(KBr) 1647, 3593 cm.sup.-1 ; MS (EI) 301
(M.sup.+), 287, 286, 217.
Anal. for C.sub.18 H.sub.23 NO.sub.3 : Calcd: C, 71.73; H, 7.69; N, 4.65.
Found: C, 72.08; H, 7.81; N, 4.40.
EXAMPLE 17
2[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]carbonyl]-1H-imidazole-5-carb
oxylic acid monohydrochloride
To a solution of 1-[(dimethylamino)methyl]imidazole (Katritzky, A. R.,
Rewcastle, G. W., Fan, W-Q., J. Org. Chem. 1988, 53, 5688 (3.02 g, 0.02
mole) in THF (75 mL) at -78.degree. is added 1.6 M n-butyllithium (14 mL,
0.022 mole). The mixture is warmed at 0.degree. C. for 20 minutes and
cooled to -78.degree. C. and a solution of
N-methoxy-N-methyl-[3,5-di-tert-butyl-4[(2
methoxyethoxy)methoxy]]benzamide (Example 6) in THF (50 mL) is added
slowly. After stirring at room temperature 17 hours and recooling to
-78.degree. C., 1.7 M tert-butyllithium (13 mL, 0.022 mole) is added. The
mixture is allowed to come to -10.degree. C. and then is recooled to
-78.degree. C. Several chunks of solid CO.sub.2 are added and the reaction
mixture is allowed to come to room temperature and 1 N HCl (100 mL) is
added. The THF is removed by concentrating and the mixture is extracted
with CH.sub.2 Cl.sub.2. The extracts are washed with brine and dried with
Na.sub.2 SO.sub.4 and evaporated. The crude product is deprotected by
allowing it to stand in 5% (w/v) HCl/MeOH (100 mL) for 50 hours. This
solution is evaporated and the residue is crystallized in 20% (w/v)
HCl/Et.sub.2 O to yield a yellow solid, 1.92 g (25%), mp>172.degree. C.;
.sup.1 H NMR (DMSO-d.sub.6) .delta.1.44 (s, 18H, tert-butyl), 7.99 (s, 2H,
aromatics), 8.49 (b, 2H, aromatic +OH), 8.6-11.0 (broad, 2H,
exchangeable); IR(KBr) 1590, 1630, 1660, 1730 (broad), 3609 cm.sup.-1 ; MS
(El) 344 (M.sup.+), 329 (M-15), 311, 300 (M-CO.sub.2).
Anal. for C.sub.19 H.sub.24 N.sub.2 O.sub.4 .multidot.HCl: Calcd: C, 59.92;
H, 6.62; N, 7.36; Cl.sup.-, 9.31. Found: C, 59.89; H, 6.83; N, 7.16;
Cl.sup.-, 8.97.
EXAMPLE 18
[3,5-Bis(1,1)dimethylethyl)-4-hydroxyphenyl]-2-thiazolylmethanone,
O-methyloxime
This compound is prepared from the compound in Example 4 according to the
method described for Example 14. There is obtained 0.877 g (54%) white
crystals, mp 113-115.degree. C.; 1H NMR 1.44 (two singlets, 18H,
tert-butyl of each oxime isomer), 4.05 and 4.22 (2s, 3H, OCH3), 5.37 and
5.45 (2s, 1H, OH), 7.31-8.00 (m, 4H, aromatics); IR(KBr) 1060, 3555, 3588
cm.sup.-1 ; MS (EI) 346 (M.sup.+), 331 (M-CH.sub.3), 315 (M-OCH.sub.3),
299.
Anal. for C.sub.19 H.sub.26 N.sub.2 O.sub.2 S: Calcd: C, 65.87; H, 7.57; N,
8.09; S, 9.26. Found: C, 66.21; H, 7.81; N, 8.06; S, 9.16.
EXAMPLE 19
[3,5-Bis(1,1-dimethylethyl) 4-hydroxyphenyl-1(1H-pyrazol-3-yl methanone 0
methyloxime (2:1 mixture of isomers)
This compound is prepared from the compound in Example 8 according to the
method described for Example 14. There is obtained 0.033 g (6%) white
crystals, mp 192-194.degree. C.; .sup.1 H NMR (CDCl.sub.3) 1.35 (s, 18H,
tert butyl), 3.9 (two singlets, 3H, CH.sub.3 oxime isomers), 6.3-7.8 (m,
5H, 4 aromatic+OH), 13.2 (two singlets, 1H, NH); IR(KBr) 1430, 1520, 3600
cm.sup.-1 ; MS (EI) 329 (M.sup.+), 314 (M-15), 298.
Anal. for C.sub.19 H.sub.27 N.sub.3 O.sub.2 : Calcd: C, 69.27; H, 8.26; N,
12.75. Found: C, 69.29; H, 8.26; N, 12.61.
EXAMPLE 20
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-(5-chloro-1,3
-dimethyl-1H-pyrazol-4-yl)methanone, O-methyloxime
This compound is prepared from the compound in Example 7 according to the
method described for Example 14. There is obtained 0.403 g (42%) yellow
crystals, mp 120-122.degree. C.; 1H NMR (DMSO-d.sub.6) .delta.1.41 (s,
18H, tert-butyl), 2.06 (s, 3H, methyl), 3.83 (s, 3H, NCH.sub.3), 4.00 (s,
3H, OCH.sub.3), 5.37 (s, 1H, OH), 7.33 (s, 2H, aromatics); IR(KBr) 1550,
1620, 3500 (broad) cm.sup.-1 ; MS (El) 391 (M.sup.+), 376 (M-CH.sub.3),
360 (M-OCH.sub.3), 344.
Anal. for C.sub.21 H.sub.30 N.sub.3 O.sub.2 Cl; Calcd: C, 64.35; H, 7.72;
N, 10.72; Cl, 9.05. Found: C, 64.45; H, 7.87; N, 10.65; Cl, 9.14.
EXAMPLE 21
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl11-2-oxazolyl methanone oxime
(single unknown oxime isomer)
This compound is prepared from the compound in Example 16 according to the
method for Example 10. There is obtained 0.297 g (57%) white crystals, mp
245-248.degree. C.; 1H NMR (DMSO-d.sub.6) .delta.1.37 (s, 18H,
tert-butyl), 7.31 (m, 4H, aromatics), 8.18 (s, 1H, OH), 11.90 (S, IH,
NOH); IR(KBr) 1550, 1633, 1653, 3622 cm.sup.-1 ; MS (EI) 316 (M.sup.+),
301, 286, 283.
Anal. for C.sub.18 H.sub.24 N.sub.2 O.sub.3 : Calcd: C, 68.33; H, 7.65; N,
8.85. Found: C, 67.95; H, 7.50; N, 8.74.
EXAMPLE 22
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-oxazolyl methanone,
0-methyloxime (4:1 mixture of oxime isomers)
This compound is prepared from the compound in Example 16 according to the
method described for Example 14. This is obtained 0.360 g (68%) white
crystals, mp 127-132.degree. C.; 1H NMR (CDD13) .delta.1.44 (two singlets,
18H, tert-butyl (2 oxime isomers present)), 4.09 (s, 3H, CH.sub.3), 5.42
and 5.47 (two singlets, 1H, OH), 7.26-7.79 (m, 4H, aromatics); IR(KBr)
1440, 3150, 3600 cm.sup.-1 ; MS (EI) 330 (M.sup.+), 315 (M-CH3), 299
(M-OCH.sub.3).
Anal. for C.sub.19 H.sub.26 N.sub.2 O.sub.3 : Calcd: C, 69.06; H, 7.93; N,
8.48. Found: C, 69.40; H, 8.06; N, 8.56.
EXAMPLE 23
[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-(hydroxyimino)methyl]-1H-imi
dazole-5-carboxylic acid (mixture of isomers)
To a solution of the compound in Example 17 (0.50 g, 0.0013 mole) and 1.47
g (0.0185 mole) pyridine in 35 mL iPrOH is added 0.452 g (0.0065 mole)
hydroxylamine hydrochloride. The reaction mixture is heated under reflux
48 hours and is evaporated. The residue is taken up in Et.sub.2 O and
washed twice with H.sub.2 O containing enough HOAc to bring pH to 4 and
once with brine. After drying with MgSO.sub.4 and evaporating the solvent
the residue is recrystallized from Et.sub.2 O-n-hexane to yield 0.22 g
white solid (47%), mp >168.degree. C.; .sup.1 H NMR (DMSO d.sub.6
+CDCl.sub.3) 1.44 (s, 18H, tert-butyl), 5.57 (broad, IH), 7.19-7.78 (m,
4H, 3 aromatics+1 exchangeable), 11.6-12.3 (broad, 1H); IR(KBr) 1701, 3630
cm.sup.-1 ; MS (EI) 359 (M.sup.+), 344, 315 (M-CO.sub.2 ).
Anal. for C.sub.19 H.sub.25 N.sub.3 O.sub.4 .multidot.0.3H.sub.2 O: Calcd:
C, 62.55; H, 7.07; N, 11.52; H.sub.2 O, 1.64. Found: C, 62.90; H, 7.14; N,
11.27; H.sub.2 O, 1.93.
EXAMPLE 24
[3,5-Bis(1,1-dimethylethyl) 4-hydroxyphenyl](1-methyl-1H-imidazol-2-yl)
methanone, O-methyloxime
To a mixture of
[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-imidazol-2-yl methanone
(Example 9) (0.41 g, 1.36 mmole) and 0.55 g (6.6 mmole) methoxylamine
hydrochloride in 35 mL i PrOH is added 0.8 g (10.0 mmole) pyridine. The
mixture is heated under reflux 48 hours and evaporated and the residue is
taken up in CH.sub.2 Cl.sub.2 and washed with 1 N HCl, two times with
saturated NaHCO.sub.3 and dried with Na.sub.2 SO.sub.4 and evaporated. The
residue is recrystallized from Et.sub.2 O-n-hexane yielding 0.305 g (63%)
of white crystals mp 222-223.degree. C.; 1H NMR (CDCl.sub.3) .delta.1.44
(s, 18H, tert-butyl), 3.98 and 4.16 (two singlets, 3H, OCH.sub.3 oxime
isomers), 5.3 and 5.4 (two singlets, 1H, OH), 7.0-7.5 (m, 4H, aromatics),
0.8-1.3 (m, 4.6H, n-hexane); IR(KBr) 1040, 1450, 3600 cm.sup.-1 ; MS (EI)
329 (M.sup.+), 314 (M CH.sub.3), 298 (M-OCH.sub.3), 282.
Anal. for C.sub.19 H.sub.27 N.sub.3 O.sub.2 .multidot.0.33C.sub.6 H.sub.14
: Calcd: C, 70.42; H, 8.91; N, 11.73. Found: C, 70.40; H, 8.87; N, 11.55.
EXAMPLE 25
[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}-(1-methyl-1H-imidazol-2-yl)met
hanone, O-methyloxime
This compound is prepared from the compound in Example 3 according to the
method for Example 14. There is obtained 0.03 g (13%) white crystals, mp
122-127.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.39 (s, 18H,
tert-butyl), 3.57 (s, 3H, NCH.sub.3), 4.00 (s, 3H, OCH.sub.3), 5.39 (s,
1H, OH), 6.99 (s, 1H, imidazole), 7.17 (s, 1H, imidazole), 7.31 (s, 2H,
phenyl); IR(KBr) 1435, 1464 cm.sup.-1 ; MS (EI) 344, 343 (M.sup.+), 328,
312, 301, 296.
Anal. for C.sub.20 H.sub.29 N.sub.3 O.sub.2 : Calcd: C, 69.94; H, 8.51; N,
12.23. Found: C, 69.68; H, 8.34; N, 11.93.
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